Comparative theobromine metabolism in five mammalian species.

Biotransformation of theobromine (TBR) was compared in rats, mice, hamsters, rabbits, and dogs by assaying urinary metabolites using HPLC after oral administration of a 5 mg/kg dose containing 8-14C-TBR. Recovery of radioactivity ranged from 60-89% of the dose in urine, and from 2-38% of the dose in feces, with most material being excreted during the first 48 hr after dosing. TBR was most extensively metabolized by rabbits and male mice. The primary metabolite excreted by rats and mice was 6-amino-5-[N-methylformylamino]-1-methyluracil (6-AMMU); male mice converted TBR to this metabolite more extensively than did female mice. Rabbits and dogs metabolized TBR primarily to 7-methylxanthine (7-MX) and 3-methylxanthine (3-MX), respectively; the major metabolites excreted by hamsters were 6-AMMU and 7-MX. Overall N-demethylase activity yielding monomethyl metabolites was greatest in rabbits and lowest in rats. Ring N-demethylation at position 3 predominated over 7-N-demethylation in all species except the rat and dog. In dogs, TBR was N-demethylated primarily at position 7, while N-demethylase activity in rats was without apparent positional specificity. Oxidation of methylated xanthines to the corresponding uric acids was a relatively minor metabolic pathway in all species, but had greatest activity in mice. Oxidation of TBR to 3,7-dimethyluric acid was significantly greater in female rats than in male rats. In summary, excretion patterns of TBR and its metabolites were qualitatively similar among species, indicating that TBR is metabolized along similar pathways. Except for the excretion of small quantities of an unidentified but apparently unique metabolite by dogs, only quantitative species- and sex-related differences were observed in the metabolic disposition of TBR.